The present invention relates to novel bicyclic compounds, stereo isomers and/or pharmaceutically acceptable salts thereof.
Atherosclerosis is generally considered an inflammatory disease—with inflammation being the cause of both initiation and progression of the lesion. Without being bound by theory, cholesterol accumulation in macrophages of atherosclerotic lesion (fatty streaks) is believed to be a contributor of localized inflammation and lesion progression. Several types of lipid particles can contribute to the formation of fatty streaks—cholesterol rich low density lipoprotein particles (LDLs) and triglyceride rich very low density lipoproteins (VLDLs) and remnant particles. Cholesterol and other lipids from these particles are typically taken by macrophages in atherosclerotic lesions leading to the formation of lipid-loaded foam cells. Atherosclerotic plaques containing lipid-loaded macrophages are typically inflammatory, are unstable, and are prone to plaque rupture. Acute coronary syndromes (ACS) are often the end manifestations of such plaque rupture, resulting in angina (chest pain), myocardial ischemia (MI, heart attack), fatal MI (sudden death), or stroke. LDL-lowering therapy may allow for remodeling of these plaques, rendering the plaques less prone to rupture. Statin-mediated remodeling processes, however, may take months to years to occur, and hence the benefit of lipid-lowering therapy may not be clinically noticed for several years, as was shown in recent statin prevention trials. Also, although statins are effective at reducing cardiovascular risk, they typically reduce risk by only about one-third over five years. Stabilizing plaque, by reducing cholesterol content or by reducing inflammation, may be important for ACS patients to minimize/prevent reoccurrence of cardiac events.
Cholesterol-loaded macrophages are typically present at all stages of atherosclerosis and are typically abundant in ruptured atherosclerotic plaques. Pathways leading to cholesterol accumulation and egress may determine the physiological (inflammatory/apoptotic) state of the macrophage. Without being bound by theory, macrophage cholesterol is thought to be removed by reverse cholesterol transport (RCT), a process that involves several players including ATP-binding cassette transporters ABCA1 and ABCG1, lecithin cholesterol acyltransferase (LCAT), and scavenger receptor, class B, type I (SR-B1). An increase in the activity of ABCA1, LCAT, and SR-B1, typically results in a boost in the arteries. The ABCA1, LCAT, and SR-B1 genes are, therefore, commonly referred to as reverse cholesterol transport RCT) genes.
Elevated levels of LDL and triglycerides and low levels of HDL are often found in diabetics. This phenotype is referred to as “diabetic dyslipidemia”. This condition may result in cholesterol accumulation, especially in tissues that are important in glucose metabolism. Cholesterol accumulation in tissues may lead tissue dysfunction. For example cholesterol accumulation in the pancreas may result in decreased secretion of insulin, the critical hormone required for glucose uptake. Cholesterol accumulation in other tissues, e.g. adipose and skeletal muscle may lead to insulin resistance and, thus, defective glucose uptake in response to insulin. Removal of cholesterol from these tissues will typically have a beneficial effect on insulin resistance, pancreatic function and, thus, is useful for prevention and treatment of diabetes.
GATA can modulate the expression of RCT proteins and pharmacological modulation of GATA can serve as a mechanism for the treatment of atherosclerosis, diabetes and its associated complications (U.S. patent application Ser. No. 12/113,426, incorporated herein by reference in its entirety). GATA transcription factor contains three domains, the C-finger, the N-finger, and the Activation Domain. The C-finger, named for being near the C-terminal, has two highly conserved zinc finger binding domains, which form the Activation Domain that binds the consensus sequence (A/T)GATA(A/G). The N-finger, named for being near the N-terminal also binds DNA and a cofactor named FOG-1. The Activation Domain is responsible for GATA's strong transcriptional activation. The gene for GATA is on the X-chromosome.